US20140147397A1 - Stable amorphous solid form of a triazine derivative and the corresponding manufacturing process - Google Patents

Stable amorphous solid form of a triazine derivative and the corresponding manufacturing process Download PDF

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Publication number
US20140147397A1
US20140147397A1 US13/750,329 US201313750329A US2014147397A1 US 20140147397 A1 US20140147397 A1 US 20140147397A1 US 201313750329 A US201313750329 A US 201313750329A US 2014147397 A1 US2014147397 A1 US 2014147397A1
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US
United States
Prior art keywords
amorphous solid
solid form
solvent
compound
ethylhexyl
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Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13/750,329
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English (en)
Inventor
Ferruccio Berte'
Francesco MAESTRI
Luca Bemporad
Massimo FABBI
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3V Sigma SpA
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3V Sigma SpA
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Filing date
Publication date
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Assigned to 3V SIGMA S.P.A. reassignment 3V SIGMA S.P.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BEMPORAD, LUCA, BERTE', FERRUCCIO, FABBI, Massimo, MAESTRI, FRANCESCO
Publication of US20140147397A1 publication Critical patent/US20140147397A1/en
Abandoned legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0241—Containing particulates characterized by their shape and/or structure
    • A61K8/0245—Specific shapes or structures not provided for by any of the groups of A61K8/0241
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
    • A61K8/4966—Triazines or their condensed derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations

Definitions

  • the present invention relates to the stable amorphous solid form of particular s-triazine derivatives, its manufacturing process and its use as a sunscreen or light stabiliser.
  • Ultraviolet solar radiation has a damaging effect on the skin tissue, and causes the degradation of polymers.
  • sunscreens which absorb the UV part of solar radiation, harmful effects and aging of the skin and polymer materials can be prevented, or at least slowed.
  • UV-B ultraviolet-B
  • a drawback shared by all these compounds is their low ability to absorb radiation between 290 and 320 nm, which means that relatively large quantities are required to obtain the optimum photoprotective effect.
  • U.S. Pat. No. 4,617,390 and 4,724,137 disclose s-triazine derivatives obtained by reacting trichlorotriazine with p-amino-benzoic acid esters, which absorb intensely in the UV-B zone.
  • p-amino-benzoic acid esters which absorb intensely in the UV-B zone.
  • solubility of these compounds in the solvents generally used to formulate sun creams is very low, which makes their practical use problematic and very difficult, especially when the percentage of photoprotector in the composition must be increased to prepare formulations with a high sun protection factor.
  • U.S. Pat. No. 4,656,272 discloses the preparation of said compound in the presence of esters of branched alkanoic acids, and its isolation in mixtures with them.
  • U.S. Pat. No. 6,531,117 discloses stable aqueous dispersions of various sunscreens including stable aqueous colloidal dispersions of said compound in its amorphous or partly amorphous form, divided at microscopic level and obtained by particular precipitation techniques from solvents in the presence of protective colloids.
  • U.S. Pat. No. 7,074,922 discloses the preparation of a tautomeric form of said compound by a particular process of precipitation of its tautomeric forms from particular mixtures of solvents.
  • the compound of formula (I) can easily be obtained, still pure, in its amorphous solid or non-crystalline form by rapid cooling of its molten mass or rapid elimination of the solvent from a solution thereof at temperatures lower than its melting point.
  • the amorphous solid form of compound (I) is stable at normal storage temperatures for long periods, and can easily be ground to a powder that is not caked, and is easy to use.
  • the amorphous form of compound (I) in the form of powder, granules or flakes is much more rapidly dissolvable in common solvents and cosmetic oils than the corresponding crystalline form, which is already known and identifiable by the existence of a precise melting point, generally between 126 and 132° C.
  • the amorphous solid form is soluble in reasonable times in cosmetic oils at much lower temperatures, and even at room temperature.
  • the amorphous solid form of compound (I) is easily identifiable by thermal analysis techniques such as differential scanning calorimetry (known as DSC).
  • the amorphous solid form presents an exothermic transition at temperatures of between 50 and 90° C., ie. much lower than the endothermal transition temperatures of the melting point of the corresponding crystalline form.
  • the values of the two transition areas are comparable, demonstrating that the substance obtained is almost totally amorphous.
  • Compound (I) in its known crystalline form does not present any exothermic transition at low temperature, only those relating to melting close to or at the melting point.
  • the first subject of the invention is therefore the amorphous solid form of the compound of formula I, characterised by exothermic transition at temperatures below 125° C., and generally between 50 and 90° C., determined by differential scanning calorimetry (DSC).
  • the invention presents as a solid with a vitreous appearance.
  • the amorphous solid form can coexist with the known crystalline form.
  • the amorphous solid form according to the present invention is preferably present in a proportion exceeding 10% by weight, more preferably exceeding 40%, and even more preferably exceeding 80% by weight.
  • the amorphous solid form of compound (I) can also be characterised by other analysis techniques, such as X-ray diffractometry and density measurements.
  • the amorphous solid form of compound (I) is obtained easily and efficiently by rapidly cooling, or supercooling, in under a few seconds or minutes, the compound melted at temperatures exceeding 126-132° C., to temperatures below 60° C., preferably below 40° C., and even more preferably below 30° C.
  • This process can be performed, for example, by pouring the molten compound onto the cold surface of a suitably cooled flaking machine or into a cold, inert non-solvent such as water, methanol, ethanol or n-heptane.
  • a suitably cooled flaking machine or into a cold, inert non-solvent such as water, methanol, ethanol or n-heptane.
  • the amorphous solid form of compound (I) can also be obtained from a solution thereof in solvent by rapidly removing the solvent, in particular at temperatures below melting point, for example with the aid of a vacuum or flow of air or inert gas such as nitrogen.
  • a solution of compound (I) is poured into a non-solvent system so that the substance precipitates and can be recovered at temperatures below melting point by known methods such as filtration and drying.
  • the solvents that can be used include alcohols such as for example ethanol, propanol, isopropanol, butanol, isobutanol, hexanol, 2-ethylhexanol, octanol and dodecanol; glycols such as propylene glycol; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; esters such as ethyl acetate and butyl acetate; aliphatic and aromatic hydrocarbons such as petrols, mineral spirits, benzene, toluene and xylene.
  • alcohols such as for example ethanol, propanol, isopropanol, butanol, isobutanol, hexanol, 2-ethylhexanol, octanol and dodecanol
  • glycols such as propylene glycol
  • ketones such as acetone
  • non-solvents that can be used include for example water, methanol, heptane and decane.
  • Compound (I) can be synthesised by the techniques already known and described in U.S. Pat. No. 4,617,390 and U.S. Pat. No. 4,724,137 cited above by reacting cyanuryl chloride with 2-ethylhexyl p-aminobenzoate in a solvent as hydrocarbon units or xylene.
  • the crystalline form of compound (I) is obtained by recrystallisation.
  • the amorphous solid form according to the present invention can also be produced in these cases from the solution of compound (I) obtained at the end of the reaction without performing the subsequent recrystallisation stages, but first eliminating the solvent and rapidly cooling the molten substance obtained or rapidly eliminating the solvent in short times at temperatures below melting point.
  • the amorphous solid form can easily be produced by melting the crystalline form at temperatures higher than its melting point (126-132° C.), followed by rapid cooling.
  • the amorphous solid form can also be obtained by dissolving the crystalline form in a solvent thereof and rapidly eliminating the solvent at temperatures below melting point.
  • the amorphous solid form of compound (I) according to the invention can be advantageously used in the form of powder, granules or flakes in plastics, coatings, cosmetic formulations, and in particular in sunscreens.
  • cosmetic formulations consist of emulsions containing an oil phase.
  • cosmetic formulations containing sunscreens such as the compound of formula (I) are generally of this type.
  • the method most commonly used for their manufacture requires the filter to be dissolved first in the oil phase, followed by production of the emulsion.
  • the dissolution rate of the sunscreen and the temperature at which said dissolution takes place in reasonable times are therefore important economic factors.
  • the amorphous solid form according to the invention can be dissolved easily in many emollients and polar oils typically used in the cosmetic field, especially in sunscreen formulations.
  • oils are (INCI Names): Hexyl Laurate, C12-13 Alkyl Lactate, PPG-3 Myristyl Ether, Propylene Glycol Monoisostearate, Di-C12-13 Alkyl Malate, C 12-13 Alkyl Octanoate, Cocoglycerides, Tridecyl Salicylate, Di-C12-13 Alkyl Tartrate, PEG-7 Hydrogenated Castor Oil, Dioctyl Adipate, Octyldodecanol, PPG-2 Myristyl Ether Propionate, Propylene Glycol Dicaprylate/Dicaprate, Isopropyl PPG-2 Isodeceth-7-Carboxylate, PEG-7 Glyceryl Cocoate, Diisopropyl Adipate, Cetearyl Isononanoate,
  • the amorphous solid form according to the invention can also be dissolved in all its typical solvents, such as for example alcohols including ethanol, propanol, isopropanol, butanol and 2-ethylhexanol, glycols such as propylene glycol, esters such as ethyl acetate and butyl acetate, ethers such as tetrahydrofuran, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, and aliphatic and aromatic hydrocarbons such as toluene and xylenes.
  • solvents such as for example alcohols including ethanol, propanol, isopropanol, butanol and 2-ethylhexanol
  • glycols such as propylene glycol
  • esters such as ethyl acetate and butyl acetate
  • ethers such as tetrahydrofuran
  • ketones such
  • the amorphous solid form according to the present invention can also be dissolved in other UVA and UVB sunscreens in the liquid state.
  • the amorphous solid form according to the present invention can also be used in less polar oils, such as liquid paraffin and dicaprylyl ether.
  • amorphous solid form according to the invention can be advantageously introduced into formulas for cosmetics, either as the only sunscreen or in combination with other known sunscreens, instead of forms obtained by known processes.
  • formulations constitute a second subject of the invention.
  • Said formulations will preferably contain one or more conventional UVA and UVB sunscreens such as those listed in Annex VII to the European Cosmetics
  • the formulations may contain, in addition to the amorphous solid form according to the invention, one or more sunscreens selected from 2-ethylhexyl p-methoxycinnamate, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone-5-sulphonic acid, 3-(4′-methylbenzylidene)-d,l-camphor, diethylhexyl butamido triazone, 4-(tert-butyl)-4′-methoxy-dibenzoylmethane, 2-cyano-3,3-diphenylacrylic acid 2-ethylhexyl ester, bis-ethylsiloxyphenol-methoxyphenyl-triazine, methylene-bis-benzotriazolyl-tetramethylbutylphenol, benzoic acid 2-(4-diethylamino-2-hydroxybenzoyl)-hexyl ester,
  • Example 1C 100 g of Uvasorb ET (3V Sigma Spa) in the form of a white crystalline powder (Sample 1C) with a melting point of 128° C., corresponding to the compound of formula (I), was melted at 150° C. to obtain a slightly viscous liquid, and poured rapidly onto a flat PTFE tray at 25° C. Within 5 minutes a fragile vitreous mass formed, which was ground and sieved below 200 microns, to obtain a white powder (Sample 1A).
  • Samples 1C and 1A were characterised by the differential scanning calorimetry (DSC) technique. Sample 1C did not present any thermal transition until the expected known endothermic melting peak at 128° C.
  • the amorphous solid sample 1A according to the present invention presented a first exothermic transition (corresponding to a formation of crystalline form) at temperatures of between 50 and 90° C., and subsequently at 128° C., the endothermic transition corresponding to melting of the crystalline form that formed at lower temperatures.
  • Sample 1A was stored for 12 months at room temperature and subjected to a second DSC measurement. Its appearance was still that of a white powder.
  • Sample 1A is therefore an amorphous, solid, stable form of the compound of formula (I).
  • Example 1 was repeated using 100 g of Uvinul T 150 (Basf) in the form of a white crystalline powder (Sample 2C) to obtain the corresponding amorphous solid form (Sample 2A).
  • sample 2A was a stable amorphous form of the compound of formula (I).
  • Example 1 according to the present invention was repeated using 100 g of compound (I) with melting point 128° C. obtained in accordance with the experimental conditions described in example 1 of U.S. Pat. No. 4,617,390.
  • the compound was melted at 140° C. followed by rapid cooling on a cold surface to 25° C. to obtain the amorphous solid form, which was ground and sieved below 200 microns (Sample 3A).
  • sample 3A was a stable amorphous form of the compound of formula (I).
  • the total dissolution time was measured, with visual inspection, noting the time of complete disappearance of any heterogeneity in the form of particles or opalescence in the solution.
  • the total dissolution time was measured, with visual inspection, noting the time of complete disappearance of any heterogeneity in the form of particles or opalescence in the solution.
  • the total dissolution time was measured, with visual inspection, noting the time of complete disappearance of any heterogeneity in the form of particles or opalescence in the solution.
  • Amorphous solid sample 1A according to the present invention was used to prepare two cosmetic formulas of oil-in-water emulsion (cosmetic formula 1 and cosmetic formula 2).
  • the sun protection factor was measured in vitro (SPF in vitro) on said two formulas with a Labsphere UV-2000S instrument, in the UV-visible zone from 290 to 400 nm.
  • SPF sun protection factor
  • the cosmetic formula was applied to Transpore tape (3M Inc.) at the concentration of 2.0 mg/cm 2 . 3 tapes were prepared for each formula, 12 readings being taken per tape, and readings with covariance >10% above the average were rejected.
  • phase I and phase II are heated separately, under stirring, at 70-75° C., until the ingredients are completely solubilised.
  • Phase II is added to phase I, maintaining the same temperature and emulsifying with a Silverson homogeniser at 3000 rpm.
  • phase III the preparation is cooled to 40° C.
  • phase IV the product obtained is discharged.
  • phase I and phase II are heated separately, under stirring, at 70-75° C., until the ingredients are completely solubilised.
  • Phase II is added to phase I, maintaining the same temperature and emulsifying with a Silverson homogeniser at 3000 rpm.
  • phase III the preparation is cooled to 40° C.
  • phase IV the product obtained is discharged.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Birds (AREA)
  • Physics & Mathematics (AREA)
  • Geometry (AREA)
  • Dermatology (AREA)
  • Cosmetics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US13/750,329 2012-11-27 2013-01-25 Stable amorphous solid form of a triazine derivative and the corresponding manufacturing process Abandoned US20140147397A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI2012A002009 2012-11-27
IT002009A ITMI20122009A1 (it) 2012-11-27 2012-11-27 Forma solida amorfa stabile di un derivato triazinico e relativo procedimento per la sua produzione

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EP (1) EP2735564A1 (it)
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021516677A (ja) * 2018-03-20 2021-07-08 ディーエスエム アイピー アセッツ ビー．ブイ．Ｄｓｍ Ｉｐ Ａｓｓｅｔｓ Ｂ．Ｖ． 局所用組成物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT202200006299A1 (it) * 2022-03-30 2023-09-30 3V Sigma S P A Processo di preparazione di forme tautomeriche di filtri solari

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3206398A1 (de) * 1982-02-23 1983-09-01 Basf Ag, 6700 Ludwigshafen S-triazinderivate und ihre verwendung als lichtschutzmittel
DE50115609D1 (de) * 2000-02-17 2010-10-14 Basf Se Wässrige Dispersion wasserunlöslicher organischer UV-Filtersubstanzen
DE10208840A1 (de) * 2002-03-01 2003-09-18 Basf Ag Verfahren zur Herstellung einer tautomeren Form von 2,4,6-Trianilino-p-(carbo-2'-ethylhexyl-1'-oxy)-1,3,5-triazin

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021516677A (ja) * 2018-03-20 2021-07-08 ディーエスエム アイピー アセッツ ビー．ブイ．Ｄｓｍ Ｉｐ Ａｓｓｅｔｓ Ｂ．Ｖ． 局所用組成物
JP7238225B2 (ja) 2018-03-20 2023-03-14 ディーエスエム アイピー アセッツ ビー．ブイ． 局所用組成物
US11931444B2 (en) 2018-03-20 2024-03-19 Dsm Ip Assets B.V. Topical composition

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ITMI20122009A1 (it) 2014-05-28

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